ES2864838T3 - Derivatives of (R) -N- (adamantyl-2-yl) pyrrolidine-2-carboxamide for cosmetic use - Google Patents

Abstract

A compound of formula (I) ** (See formula) ** in which n, m and p are independently of each other 0 or 1, if n is 1, then q is 1 or 2, R1 is selected from the group consisting of H , C1-C6 acyl or hydroxyacetyl, R2 is H or C1-C6 alkyl, and R3 is selected from the group consisting of H, C1-C6 alkyl, C1-C6 aralkyl, C1-C6 heteroarylalkyl, and C1-C6 biphenylalkyl, in which that the aryl, heteroaryl or biphenyl aromatic residue may be optionally substituted, or a cosmetically acceptable salt thereof.

Description

DESCRIPTION

Derivatives of (R) -N- (adamantyl-2-yl) pyrrolidine-2-carboxamide for cosmetic use

The present invention relates to novel selective 11 -beta-hydroxysteroid dehydrogenase type 1 (11P-HSD1) inhibitors and the use thereof to prevent age-induced skin structure and function defects.

Excess glucocorticosteroids (GC) adversely affects skin integrity, inducing thinning and impaired wound healing. Aged skin, such as photo-exposed skin in particular, shares a similar phenotype. Elevated 11P-HSD1 activity in aging skin leads to increased local GC generation, which may account for age-associated alterations in dermal integrity such as dermal and epidermal thinning, increased skin fragility, decreased dermal collagen and increased transepidermal water loss. Furthermore, the increased local concentration of GC results in poor wound healing [Tiganescu et al., J. Clin Invest. 2013; 123 (7): 3051-3060].

Thus, topical administration of an effective amount of an 11P-HSD1 inhibitor is useful in treating age-associated disturbances in dermal integrity and wound healing. Long-term treatment with an 11P-HSD1 inhibitor is also helpful in delaying the onset of aging.

WO 2005/108359, WO 2007/057768 and US 2005/245533 disclose certain proline and morpholine derivatives as 11P-HSD1 inhibitors used to treat, for example, diabetes, metabolic syndrome, insulin resistance syndrome, obesity, glaucoma and hyperinsulinemia.

Su Xiandong et al. (Bioorganic & Medicinal chemistry, vol. 20, no. 21, pages 6394-6402) refers to certain adamantyl carboxamide and acetamide derivatives as potent inhibitors of 11P-HSD1.

Surprisingly, it has been discovered that compounds of formula (I) comprising a residue of (R) -N- (adamantyl-2-yl) pyrrolidine-2-carboxamide

where n, m, and p are independently 0 or 1,

if n is 1, then q is 1 or 2,

R1 is selected from the group consisting of H, C ¹ -C ⁶ acyl, or hydroxyacetyl,

R2 is H or C ¹ -C ⁶ alkyl, and

R3 is selected from the group consisting of H, C ¹ -C ^6, aralkyl C ¹ -C ⁶ heteroarylalkyl ^C1 - ^C6 and biphenylalkyl C ¹ -C 6, in which the aromatic residue aryl, heteroaryl or biphenyl may be optionally substituted,

or a cosmetically acceptable salt thereof are very effective 11P-HSD1 inhibitors and therefore particularly suitable for incorporation into cosmetic compositions for the treatment of age-associated alterations in dermal integrity and wound healing.

The respective (S) -isomers as well as the respective 1-adamantyl derivative show no or only very limited activity.

Therefore, in a first aspect, the present invention relates to a compound of formula (I)

where n, m, and p are independently 0 or 1,

if n is 1, then q is 1 or 2,

R1 is selected from the group consisting of H, C ¹ -C ⁶ acyl, or hydroxyacetyl,

R2 is H or C ¹ -C ⁶ alkyl, and

R3 is selected from the group consisting of H, C ¹ -C ^6, aralkyl C ¹ -C ⁶ heteroarylalkyl ^C1 - ^C6 and biphenylalkyl C ¹ -C 6, in which the aromatic residue aryl, heteroaryl or biphenyl may be optionally substituted,

0 a cosmetically acceptable salt thereof.

Aromatic residues aryl, heteroaryl and aralkyl biphenyl C ¹ -C ⁶ heteroarylalkyl ^C1 - ^C6 and ^C1 - ^C6 biphenylalkyl may be unsubstituted or substituted with one or more substituents. In all embodiments of the present invention, such substituents are preferably selected from halogen, hydroxy, nitro, cyano, C ¹ -C ⁶ alkoxy and ^C1 - ^C6 alkanoyloxy ^C1 - ^C6. More preferably, in all embodiments of the present invention, the heteroaryl and biphenyl residues are unsubstituted, while the aryl residues are substituted with a substituent selected from the group consisting of F, Cl, hydroxy, cyano, C ^{1 alkyl} -C ³ alkoxy C ¹ -C ³ alkanoyloxy and C ¹ -C ^3, preferably of the group consisting of F, hydroxy, cyano, (m) ethoxy and acetoxy.

The term "C ¹ -C ⁶ alkyl" refers to ^{unbranched C 1} -C ⁶ alkyl or branched C ³ -C ⁶ alkyl groups such as methyl, ethyl, n-propyl, 1-methylethyl, n-butyl, 1 -methylpropyl, 2-methylpropyl, 1,1-dimethylethyl, n-pentyl, 1-methylbutyl, 2-methylbutyl, 3-methylbutyl, 2,2-dimethylpropyl, 1-ethylpropyl, n-hexyl, 1,1-dimethylpropyl, 1 , 2-dimethylpropyl, 1-methylpentyl, 2-methylpentyl, 3-methylpentyl, 4-methylpentyl, 1,1-dimethylbutyl, 1,2-dimethylbutyl, 1,3-dimethylbutyl, 2,2-dimethylbutyl, 2,3-dimethylbutyl , 3,3-dimethylbutyl, 1-ethylbutyl, 2-ethylbutyl, 1,1,2-trimethylpropyl, 1,2,2-trimethylpropyl, 1-ethyl-1-methylpropyl and 1-ethyl-2-methylpropyl.

The term "C ¹ -C ⁶ acyl" refers to a -C (= O) C ¹ -C ⁶ alkyl group such as acetyl, propionyl, n-butyryl, isobutyryl, pentanoyl, hexanoyl and heptanoyl groups.

The term "C ¹ -C ⁶ aralkyl" refers to a -C ^{1 -C 6} alkyl aryl, where the term "aryl" is, for example, a phenyl, indanyl or naphthyl group.

The term "C ¹ -C ⁶ heteroarylalkyl" refers to a -C ^{1 -C 6} alkyl-heteroaryl, where the term "heteroaryl" refers to a 5- or 6-membered aromatic ring containing one or more heteroatoms, specifically, N, O, or S; these heteroaromatic rings can be fused to other aromatic systems.

The term "C ¹ -C ⁶ biphenylalkyl" refers to a -C ^{1 -C 6} -alkyl-biphenyl, where the term biphenyl refers to a 1,1'-biphenyl which may be attached at the o-position, myp to the ^{C 1} -C ⁶ alkyl residue.

The term "C ¹ -C ⁶ alkanoyloxy" refers to a -OC (= O) C ¹ -C ⁶ alkyl group such as acetyloxy, propionyloxy, n-butyryloxy, iso-butyryloxy, pentanoyloxy, hexanoyloxy, and heptanoyloxy groups.

It is well understood that the present invention encompasses the compounds of formula (I) as optically pure isomers such as, for example, as enantiomers or pure stereoisomers, as well as mixtures of different isomers such as, for example, as racemates or mixtures of diastereoisomers.

The term "or a cosmetically acceptable salt thereof" refers to compounds of formula (I) in the form of an acid addition salt such as in the form of a chloride, acetate or trifluoroacetate salt. Alternatively, the salt may be formed by reaction with an alkaline or alkaline earth base which produces the respective alkaline or alkaline earth salt such as, in particular, the respective lithium, sodium, potassium, magnesium or calcium salts. Much more preferred in all embodiments of the present invention are the compounds of formula (I) as is or in the form of their acetates or trifluoroacetates (ie, as 2,2,2-trifluoroacetates). Such salts are easily prepared by a person skilled in the art.

In all embodiments of the present invention, R1 is preferably selected from the group consisting of H and C ¹ -C ² acyl, most preferably H and acetyl.

In all embodiments of the present invention, R 2 is preferably selected from the group consisting of H and C ¹ -C ² alkyl, most preferably H and methyl.

In all embodiments of the present invention, R3 is preferably selected from the group consisting of H, C ¹ -C ² alkyl, aralkyl C ¹ -C ² which may be substituted with a substituent selected from the group consisting of F, Cl, hydroxy, cyano, C ¹ -C ³ alkyl, C ¹ -C ³ alkoxy and C ¹ -C ³ alkanoyloxy, preferably F, hydroxy, cyano, (m) ethoxy and acetyloxy, C ¹ -C heteroarylalkyl ² unsubstituted and an unsubstituted C ¹ -C ² biphenylalkyl. Most preferably in all embodiments of the present invention, R3 is selected from the group consisting of H, methyl, 3-hydroxybenzyl, 4-hydroxybenzyl, 4-methoxybenzyl, 4-ethoxybenzyl, 4-acetoxybenzyl, 4-fluorobenzyl, 2-cyanobenzyl , 4-cyanobenzyl, 1,1'-biphenyl-3-ylmethyl and 1 H-indol-3-ylmethyl.

In a particular advantageous embodiment, the present invention relates to compounds of formula (I)

where n, m, and p are independently 0 or 1,

if n is 1, then q is 1,

R1 is H or acetyl,

R2 is H or methyl, and

R3 is selected from the group consisting of H, methyl, 3-hydroxybenzyl, 4-hydroxybenzyl, 4-methoxybenzyl, 4-ethoxybenzyl, 4-acetoxybenzyl, 4-fluorobenzyl, 2-cyanobenzyl, 4-cyanobenzyl, 1 H-indole-3 -ylmethyl and 1,1'-biphenyl-3-ylmethyl,

or a cosmetically acceptable salt thereof, such as preferably a trifluoroacetate.

In a very advantageous embodiment, the compounds of formula (I) are compounds of formula (II)

with all definitions and preferences for R1 and R3 as summarized above.

Even more preferred are compounds of formula (II), wherein R1 is H or acetyl and R3 is selected from the group consisting of H, methyl, 3-hydroxybenzyl, 4-hydroxybenzyl, 4-methoxybenzyl, 4-ethoxybenzyl, 4- acetoxybenzyl, 4-fluorobenzyl, 2-cyanobenzyl, 4-cyanobenzyl, 1H-indol-3-ylmethyl and 1,1'-biphenyl-3-ylmethyl or a cosmetically acceptable salt thereof such as preferably a trifluoroacetate.

In another highly advantageous embodiment, the compounds of formula (I) are compounds of formula (III), more preferably of formula IV

with all the definitions and preferences given above for R1, R2 and R3.

Even more preferred are compounds of formula (III), such as in particular of formula (IV) in which R1 is H or acetyl, preferably H and R2 and R3 are independently of each other H or methyl or a cosmetically acceptable salt thereof such as preferably a trifluoroacetate.

Table 1 lists the most preferred compounds of (I) according to the present invention:

The compounds according to the present invention can be prepared from H-D-Pro-NH-2-Ad by conventional methods in peptide chemistry as illustrated in the examples.

In yet another embodiment, the present invention relates to the use of a compound of formula (I) with all the definitions and preferences given in this document as an inhibitor of 11 p-HSD1, in particular for the treatment of disorders associated with age in dermal integrity and wound healing and associated symptoms such as wrinkles and fine lines. Furthermore, the compounds of formula (I) are particularly suitable for avoiding defects in the structure and function of the skin induced by (photo) aging such as thinning of the skin and formation of wrinkles.

Therefore, the invention also relates to a cosmetic composition comprising at least one compound of formula (I) and a cosmetically acceptable vehicle.

The amount of the compound of formula (I) in the cosmetic composition can easily be adjusted by a person skilled in the art to achieve the desired beneficial effect. Preferably, the amount of the compound of formula (I) in the cosmetic compositions according to the present invention is at least 1 ppm based on the total weight of the cosmetic composition. In all embodiments of the present invention, the amount of the compound of formula (I) is preferably selected in the range of about 0.00001 to 0.5% by weight, more preferably in the range of 0.0001 to 0.25% by weight, much more preferably in the range of 0.0001 to 0.1% by weight, based on the total weight of the cosmetic composition.

Furthermore, the invention also relates to a method for smoothing wrinkles and fine lines and / or for reducing their volume and depth, said method comprising the step of applying a cosmetic composition according to the present invention with all definitions and preferences given in this document to the affected area.

The term "cosmetic composition" refers to compositions that are used to treat, care for or improve the appearance of the skin and / or the scalp. Particular advantageous cosmetic compositions are skin care compositions.

The cosmetic compositions according to the invention are preferably intended for topical application, which is to be understood as external application to keratinous substances, such as in particular the skin.

The term "cosmetically acceptable vehicle", as used herein, refers to a physiologically acceptable medium that is compatible with keratinous substances. Suitable vehicles are well known in the art and are selected based on the end use application. Preferably, the vehicles of the present invention are suitable for application to the skin (eg sunscreens, creams, milks, lotions, masks, serums, hydrodispersions, foundation, creams, cream gels or gels). Such carriers are well known to those skilled in the art, and may include one or more compatible liquid and solid fillers, diluents, excipients, additives, or carriers that are suitable for application to the skin. The exact amount of carrier will depend on the level of the compound of formula (I) and any other optional ingredients that one skilled in the art would classify as other than carrier (eg other active ingredients). The compositions of the present invention preferably comprise from about 75% to about 99.999%, more preferably from about 85% to about 99.99%, even more preferably from 90% to about 99%, and most preferably from about 93% to about 98% by weight of the composition, of a vehicle.

The compositions of the present invention can be formulated into a wide variety of product types, including creams, waxes, pastes, lotions, milks, foams, gels, oils, tonics, and sprays. Preferably, the compounds of formula (I) are formulated in lotions, creams, gels and tonics. These product forms can be used for various applications including, but not limited to, hand and body lotions, facial moisturizers, anti-aging preparations, makeup including foundation, and the like. Any additional components required to formulate such products vary with the type of product and can be routinely chosen by one of ordinary skill in the art.

If the compositions of the present invention are formulated as an aerosol and applied to the skin as a spray product, a propellant is added to the composition.

Compositions according to the present invention can be prepared by methods conventional in the art such as, for example, mixing a compound of formula (I) with all the definitions and preferences given herein with the cosmetically acceptable carrier. The cosmetic compositions of the invention (including the vehicle) may further comprise conventional cosmetic adjuvants and additives, such as preservatives / antioxidants, fatty / oil substances, water, organic solvents, silicones, thickeners, softeners, emulsifiers, antifoaming agents, aesthetic components such as fragrances, surfactants, fillers, anionic, cationic, nonionic or amphoteric polymers or mixtures thereof, propellants, acidifying or basifying agents, dyes, coloring / coloring agents, abrasives, absorbents, chelating agents and / or sequestering agents, essential oils, skin sensitizers, astringents, pigments or any other ingredient usually formulated in said compositions.

According to the present invention, cosmetic compositions according to the invention may also further comprise cosmetically active ingredients conventionally used in cosmetic compositions. Exemplary active ingredients include skin brightening agents; UV filters, agents for the treatment of hyperpigmentation; agents for the prevention or reduction of inflammation; firming, moisturizing, softening and / or energizing agents, as well as agents to improve the elasticity and barrier of the skin.

Examples of excipients, diluents, adjuvants, additives, as well as other cosmetic active ingredients commonly used in the skin care industry that are suitable for use in the cosmetic compositions of the present invention are described, for example, in the International Cosmetic Ingredient Dictionary & Handbook by the Personal Care Product Council (http://www.personalcarecouncil.org/), accessible online at INFO BASE (http://online.personalcarecouncil.org/jsp/Home.jsp), not limited to it.

The necessary amounts of the active ingredients, as well as the excipients, diluents, adjuvants, cosmetic additives can easily be determined by those skilled in the art based on the desired form of the product and its application. Additional ingredients can be added to the oil phase, the water phase, or separately as appropriate.

The cosmetically active ingredients useful herein may, in some cases, provide more than one benefit or function by more than one mode of action.

Of course, one skilled in the art will take care to select the aforementioned optional additional ingredients, adjuvants, diluents and additives and / or their amounts so that the advantageous properties intrinsically associated with the combination according to the invention are not adversely affected. , or not substantially, by the intended addition or additions.

The cosmetic compositions according to the present invention may be in the form of a suspension or dispersion in solvents or fatty substances or, alternatively, in the form of an emulsion or microemulsion (in particular of the oil-in-water (O / W) or water-in-oil (W / O), silicone-in-water (Si / W) or water-in-silicone (W / Si) type, PIT emulsion, multiple emulsion (for example, oil-in-water-in-oil type (O / W / O) or water in oil in water (W / O / W)), Pickering emulsion, hydrogel, alcohol gel, lipogel, single or multiple phase solution or vesicular dispersion or other common forms, which can also be applied by pencils, such as masks or as sprays.

If the cosmetic composition is an emulsion, such as in particular an O / W, W / O, Si / W, W / Si, O / W / O, multiple W / O / W or Pickering emulsion, then the amount of the The oil phase present in said cosmetic emulsions is preferably at least 10% by weight, such as in the range of 10 to 60% by weight, preferably in the range of 15 to 50% by weight, much more preferably in the range of 15 to 40% by weight, based on the total weight of the cosmetic composition.

In one embodiment, the cosmetic compositions according to the present invention are advantageously in the form of an oil-in-water (O / W) emulsion comprising an oil phase dispersed in an aqueous phase in the presence of an O / W emulsifier. The preparation of such O / W emulsions is well known to those skilled in the art.

If the cosmetic composition according to the invention is an O / W emulsion, then it advantageously contains at least one O / W or Si / W emulsifier selected from the list of, glyceryl citrate stearate, glyceryl stearate SE (self-emulsifying), stearic acid, stearic acid salts, polyglyceryl-3-methylglucose distearate. Additional suitable emulsifiers are phosphate esters and salts thereof such as cetyl phosphate (eg as Amphisol® A from DSM Nutritional Products Ltd.), diethanolamine cetyl phosphate (eg as Amphisol® DEA from DSM Nutritional Products Ltd.), potassium cetyl phosphate (for example, as Amphisol® K from DSM Nutritional Products Ltd.), sodium cetearyl sulfate, sodium glyceryl oleate phosphate, hydrogenated plant glyceride phosphate, and mixtures thereof. Additional suitable emulsifiers are sorbitan oleate, sorbitan sesquioleate, sorbitan isostearate, sorbitan trioleate, cetearyl glucoside, lauryl glucoside, decyl glucoside, sodium stearoyl glutamate, sucrose polystearate and hydrated polyisobutene. In addition, one or more synthetic polymers can be used as an emulsifier. For example, PVP eicosne copolymer, acrylates / C10-30 alkyl acrylate crospolymer, and mixtures thereof.

The at least one emulsifier O / W, respectively Si / W is preferably used in an amount of 0.5 to 10% by weight, in particular in the range of 0.5 to 6% by weight, such as more particularly in the range of 0.5 to 5% by weight, such as much more particularly in the range of 1 to 4% by weight, based on the total weight of the cosmetic composition.

Particular suitable O / W emulsifiers for use in cosmetic compositions according to the invention encompass phosphate ester emulsifiers such as, advantageously, 8-10 alkyl ethyl phosphate, C9-15 alkyl phosphate, ceteareth-2 phosphate, phosphate ceteareth-5, ceteth-8 phosphate, ceteth-10 phosphate, cetyl phosphate, pareth-4 C6-10 phosphate, pareth-2 C12-15 phosphate, pareth-3 C12-15 phosphate, DEA-ceteareth-2, DEA-cetyl phosphate, DEA-oleth-3 phosphate, potassium cetyl phosphate, deceth-4 phosphate, deceth-6 phosphate, and trilaureth-4 phosphate.

A particular suitable O / W emulsifier for use in cosmetic compositions according to the invention is potassium cetyl phosphate, for example, commercially available as Amphisol® K from DSM Nutritional Products Ltd Kaiseraugst.

Another particular suitable class of O / W emulsifiers are nonionic self-emulsifying systems derived from olive oil, for example, known as (INCI name) cetearyl olivate and sorbitan olivate (chemical composition: sorbitan ester and cetearyl ester of fatty acids olive oil) sold under the trademark OLIVEM 1000.

In a particular embodiment, the invention relates to cosmetic compositions with all the definitions and preferences given in this document in the form of O / W emulsions that comprise an oil phase dispersed in an aqueous phase in the presence of an O / W emulsifier in which the O / W emulsifier is potassium cetyl phosphate. The amount of oil phase in said O / W emulsions is preferably at least 10% by weight, more preferably in the range of 10 to 60% by weight, much more preferably in the range of 15 to 50% by weight, such as in the range of 15 to 40% by weight.

Cosmetic compositions according to the invention generally have a pH in the range of 3 to 10, preferably a pH in the range of 4 to 8, and most preferably a pH in the range of 4 to 7.5. The pH can easily be adjusted as desired with suitable acids, such as, for example, citric acid, or bases, such as sodium hydroxide (for example, as aqueous solution), triethanolamine (TEA Care), tromethamine (Trizma Base) and aminomethyl propanol (AMP-Ultra PC 2000), according to methods conventional in the art.

The amount of the cosmetic composition to be applied to the skin is not crucial and can be easily adjusted by a person skilled in the art. Preferably, the amount is selected in the range of 0.1 to 3 mg / cm2 of skin, such as preferably in the range of 0.1 to 2 mg / cm2 of skin and much more preferably in the range of 0.5 to 2 mg / cm2 of skin.

Additional suitable uses of the compounds according to the present invention encompass pharmaceutical applications. Therefore, the compounds according to the present invention can be used to prepare a pharmaceutical composition for the treatment, prevention and / or prophylaxis of any disorder and disease where it is desirable to inhibit 11 p-HSD1 in a patient in need, such as, for example, for the treatment, prevention and / or prophylaxis of conditions, disorders or diseases of metabolic syndrome, insulin resistance, dyslipidemia, hypertension, obesity, type 2 diabetes, impaired glucose tolerance (IGT), impaired blood glucose in fasting, as well as diabetic complications including cardiovascular diseases, arteriosclerosis, atherosclerosis, neurodegenerative and psychiatric disorders. The compounds according to the present invention may also be useful in slowing or preventing the progression of IGT to type 2 diabetes, as well as metabolic syndrome in type 2 diabetes. The compounds can be applied topically, orally, as well as parenterally without limit yourself to it.

The invention is further illustrated with reference to the following examples, in which all percentages are by weight based on weight based on total weight unless otherwise specified.

Experimental part

1. General Information

Abbreviations:

AA Amino Acid

Ad adamantyl

Boc tert-butyloxycarbonyl

DCM dichloromethane

DIPEA W, W-diisopropylethylamine

DMAP W, W-dimethylaminopyridine

DMF dimethylformamide

Fmoc fluorenylmethoxycarbonyl

HPLC High Pressure Liquid Chromatography

Pro proline

TFA trifluoroacetic acid

TBTU O- (benzotriazol-1-yl) -W, W, W ', W'-tetramethyluronium tetrafluoroborate

Preparative HPLC purifications: performed on Waters LC-2525 high performance liquid chromatography equipped with a Waters 2767 sample handler and a Waters FCII automated fraction collector, using a Grom Saphir 110 C18 10 gm 50 x 300 mm2 preparative column and a Waters 2487 dual wavelength UV-Vis detector operating at 220 and 254 nm.

0.07% H ² O TFA (phase A ") and MeCN 0.07% TFA (phase B") were used as eluents, with a flow rate of 55 ml / min.

2. Synthetic strategies

Synthesis of the precursor: HD-Pro-NH-2Ad * HCl

A suspension of 2.48 g (13.2 mmol, 1.1 equiv.) Of 2-adamantylamine hydrochloride is suspended in 15 ml of DMF and 2.31 ml (13.2 mmol, 1.1 equiv.) Of DIPEA . 12 mmol of Boc-D-Pro-OH are dissolved in 15 ml of DMF, then 3.85 g (12 mmol, 1 equiv.) Of TBTU and 6.9 ml (39.6 mmol, 3.3 equiv. .) of DIPEA. After 4 minutes, the pre-activated amino acid solution is added to the 2-adamantylamine hydrochloride suspension. After 60 minutes at room temperature, the reaction mixture is transferred to a separatory funnel with ethyl acetate and water. The aqueous phase is re-extracted with ethyl acetate. The combined organic phases are washed with 5% NaHCO3, ^{1M KHSO 4,} and brine. The organic phase is dried over Na2SO4 and all volatiles are removed in a water bath at 2 mbar / 40 ° C.

The residue is diluted in ethyl acetate and treated with 47 ml of 2M HCl in diethyl ether and 66 ml of 4M HCl in dioxane. The mixture is stirred overnight, concentrated in vacuo, and diluted with 200 ml of diethyl ether. The precipitate is filtered and dried. Yield: 3.32 g (11.5 mmol, 96%).

Procedure 1: Ac-AA1 -D-Pro-NH-2-Ad

214 mg (0.75 mmol, 1.0 equiv.) Of HD-Pro-NH-2Ad * HCl obtained as summarized above are dissolved in 2.5 ml of DMF and 0.13 ml (0.75 mmol, 1 , 0 equiv.) Of DIPEA. In a separate beaker, the acetylated amino acid AA1 is pre-activated as follows for 4 minutes by adding 277 mg (0.863 mmol, 1.15 equiv.) Of TBTU and 0.432 ml (2.475 mmol, 3.3 equiv.) Of DIPEA to a solution of 0.863 mmol (1.15 equiv.) Of Ac-AA1-OH in 2.5 ml of DMF. The solutions are combined and allowed to react for one hour at room temperature. The reaction mixture is transferred to a separatory funnel with ethyl acetate and water. The aqueous phase is re-extracted with ethyl acetate. The combined organic phases are washed with 5% NaHCO3, ^{1M KHSO 4,} and brine. The organic phase is dried over Na2SO4 and all volatiles are removed in a water bath at 2 mbar / 40 ° C. The respective crude products are purified by preparative HPLC.

(I-a): AA1 = Beta-alanine: 227 mg (0.62 mmol, 83%)

(I-b): AA1 = Glycine: 211 mg (0.60 mmol, 80%)

Procedure 2a: H-AA2-D-Pro-NH-2-Ad * TFA

427 mg (1.5 mmol, 1.0 equiv.) Of HD-Pro-NH-2Ad * HCl obtained as summarized above are dissolved in 5 ml of DMF and 0.26 ml (1.5 mmol, 1.0 equiv.) of DIPEA. In a separate beaker, the acetylated amino acid Fmoc AA2 is pre-activated as follows for 4 minutes by adding 1.15 equiv. of TBTU and 3.3 equiv. of DIPEA to a solution of 1.15 equiv. of Fmoc-AA2-OH in 5 ml of DMF. The solutions are combined and allowed to react for one hour at room temperature. The reaction mixture is transferred to a separatory funnel with ethyl acetate and water. The aqueous phase is re-extracted with ethyl acetate. The combined organic phases are washed with 5% NaHCO3, ^{1M KHSO 4,} and brine. The organic phase is dried over Na2SO4 and all volatiles are removed in a water bath at 2 mbar / 40 ° C. The crude Fmoc protected material is dissolved in 15 ml of DCM and treated with 50 equiv. of diethylamine for 2 hours. The respective crude products are purified by preparative HPLC.

(I-c) AA2 = L-tyrosine: 311 mg (0.58 mmol, 39%)

(I-d): AA2 = L-tryptophan: 208 mg (0.37 mmol, 50%) (0.75 mmol scale)

Procedure 2b: H-AA2-D-Pro-NH-2-Ad * TFA

The amino acid Boc AA2 as indicated below is pre-activated by adding 1.0 equiv. of TBTU and 3.3 equiv. of DIPEA to a solution of 1.0 equiv. of Boc-AA2-OH in 5 ml of DMF. After 4 minutes,

0.542 mmol (1.0 equiv.) of HD-Pro-NH-2Ad * HCl are added. The mixture is allowed to react for one hour at room temperature. The reaction mixture is transferred to a separatory funnel with ethyl acetate and water. The combined organic phases are washed with 5% NaHCO3, ^{1M KHSO 4,} and brine. The organic phase is dried over Na2SO4 and all volatiles are removed in a water bath at 2 mbar / 40 ° C. The crude Boc protected material is dissolved in 20 ml / 4 M HCl in dioxane for 45 minutes. The crude product is purified by preparative HPLC.

(I-g): AA2 L-3-phenyl-phenylalanine: 221 mg (0.37 mmol, 72%)

(I-i): AA2 = L-3- (3-hydroxyphenyl) alanine: 85 mg (0.16 mmol, 32%)

(I-k): AA2 = L-3- (4-ethoxyphenyl) alanine: 246 mg (0.78 mmol, 78%) (1 mmol scale)

Procedure 2c: HO-methyl-Tyr-D-Pro-NH-2-Ad

L-Boc-O-methyl-tyrosine-OH is pre-activated by adding 1.0 equiv. of TBTU and 3.3 equiv. of DIPEA to a solution of 1.0 equiv. of Boc-AA2-OH in 5 ml of DMF. After 4 minutes, 4.5 mmol (1.0 equiv.) Of HD-Pro-NH-2Ad * HCl is added. The mixture is allowed to react for one hour at room temperature. The reaction mixture is transferred to a separatory funnel with ethyl acetate and water. The combined organic phases are washed with 5% NaHCO3, ^{1M KHSO 4,} and brine. The organic phase is dried over Na2SO4 and all volatiles are removed in a water bath at 2 mbar / 40 ° C. The crude Boc protected material is dissolved in 20 ml / 4 M HCl in dioxane for 45 minutes. The pH of the solution is adjusted to 8 by NaHCO3 and the free base is extracted with ethyl acetate. The organic phase is dried over Na2SO4 and all volatiles are removed in a water bath at 2 mbar / 40 ° C. The intermediate is used without further purification in procedure 3 and 6.

(Intermediate 1): AA2 = L-O-methyl-tyrosine 2105 mg (4.5 mmol,> 99%)

Procedure 2d: H-AA2-D-Pro-NH-2-Ad * HCl

The amino acid Boc AA2 as indicated below is pre-activated by adding 1.0 equiv. of TBTU and 4 equiv. of DIPEA to a solution of 1.0 equiv. of Boc-4-Fluoro-Fe-OH in 5 ml of DMF. After 4 minutes, 1.5 mmol (1.0 equiv.) Of HD-Pro-NH-2Ad * HCl is added. The mixture is allowed to react for one hour at room temperature. The reaction mixture is transferred to a separatory funnel with ethyl acetate and water. The combined organic phases are washed with 5% ^{NaHCO 3 , 1 M KHSO 4,} and brine. The organic phase is dried over Na ² SO ⁴ and all volatiles are removed in a 2 mbar / 40 ° C water bath. The crude Boc-protected material is dissolved in 25 ml / 4 M HCl in dioxane for 30 minutes. The hydrochloride is precipitated by adding 100 ml of diisopropyl ether, filtered off and dried.

(Intermediate 2): AA2 = L- (4-fluoro-phenyl) alanine 573 mg (1.26 mmol, 84%)

(Intermediate ³ ): AA2 = L- (2-cyano-phenyl) alanine 443 mg (0.97 mmol, 97%) experiment performed at 1.0 mmol scale

Procedure 3: Ac-AA2-D-Pro-NH-2-Ad

0.5 mmol (1.0 equiv.) Of H-AA2-D-Pro-NH-2-Ad from procedure 2a to 2d are suspended or dissolved in 2 ml of DCM. Add a mixture of 47 microliters of acetic anhydride, 47 microliters of pyridine in 1 ml of DCM. After 15 minutes, add an additional 47 microliters of acetic anhydride, 47 microliters of pyridine in 1 ml of DCM. After 15 minutes, the reaction mixture is transferred to a separatory funnel with ethyl acetate and 5% NaHCO3. The organic phase is washed with 5% NaHCO3, ^{1M KHSO 4,} and brine. The organic phase is dried over Na2SO4 and all volatiles are removed in a water bath at 2 mbar / 40 ° C. The crude product is purified by preparative HPLC.

(I-e): 142 mg (0.31 mmol, 63%)

(I-f): 41 mg (0.08 mmol, 16%)

(I-h): 317 mg (0.69 mmol, 55%)

(I-l): 246 mg (0.53 mmol, 43%) (experiment performed at 1.25 mmol scale)

(I-n): 408 mg (0.86 mmol, 57%) (experiment performed at 1.5 mmol scale)

(I-s): 321 mg (0.69 mmol, 69%) (experiment performed at 1.0 mmol scale)

Procedure 4: Gly-LO-methyl-Tyr-D-Pro-NH-2-Ad * TFA

0.75 mmol (1.0 equiv.) Of HO-methyl-Tyr-D-Pro-NH-2-Ad from procedure 2c is dissolved in DMF. 0.788 mmol (1.1 equiv.) Of Boc-Gly-OH is preactivated in DMF by adding 1.1 equiv. of t Bt U and 1.9 equiv. by DIPEA. After 4 minutes, the solutions are combined and allowed to react for one hour at room temperature. The reaction mixture is transferred to a separatory funnel with ethyl acetate and water. The aqueous phase is re-extracted with ethyl acetate. The combined organic phases are washed with 5% NaHCO3, ^{1M KHSO 4,} and brine. All volatile compounds are removed in a water bath at 2 mbar / 40 ° C. The crude Boc-protected material is dissolved in 10 ml of 4M HCl in dioxane for 45 minutes. The crude product is purified by preparative HPLC.

(Ij): 276 mg (0.46 mmol, 61%)

Procedure 5: H-AA3-AA2-NH- (CH2) 2-D-Pro-NH-2-Ad * TFA

4 mmol of H-D-Pro-NH-2Ad * HCl prepared as outlined above are dissolved in 50 ml of acetonitrile and 12 mmol of DIPEA. 6 mmol of tert-butyl (2-bromoethyl) carbamate was added and the mixture was stirred overnight. An additional 0.58 mmol of tert-butyl (2-bromoethyl) carbamate was added and the mixture was stirred overnight. An additional 0.58 mmol of tert-butyl (2-bromoethyl) carbamate was added and the mixture was stirred overnight. All volatiles are removed in a 2 mbar / 40 ° C water bath and the residue is purified by preparative HPLC.

The crude Boc- NH- (CH2) 2-D-Pro-NH-2-Ad is dissolved in 10 ml of dioxane and 2 ml of TFA overnight. All volatile compounds are removed in a water bath at 2 mbar / 40 ° C. H2N- (CH2) 2-D-Pro-NH-2-Ad * TFA is dissolved in DMF and 2 equiv. by DIPEA. 1.1 equiv. of Boc-AA2-OH in DMF adding 1.1 equiv. of TBTU and 3.3 equiv. by DIPEA. After 4 minutes, the solutions are combined and allowed to react for one hour at room temperature. The reaction mixture is transferred to a separatory funnel with ethyl acetate and water. The organic phase is washed with 5% NaHCO3, ^{1M KHSO 4,} and brine. All volatile compounds are removed in a water bath at 2 mbar / 40 ° C. The crude Boc-AA2-NH- (CH2) 2-D-Pro-NH-2-Ad is dissolved in 15 ml of 4M HCl in dioxane overnight. All volatile compounds are removed in a water bath at 2 mbar / 40 ° C. H-AA2-NH- (CH2) 2-D-Pro-NH-2-Ad * HCl are dissolved in DMF and 2 equiv. by DIPEA. 1.5 equiv. of Boc AA3-OH in DMF adding 1.5 equiv. of TBTU and 4.5 equiv. by DIPEA. After 4 minutes, the solutions are combined and allowed to react for one hour at room temperature. All volatile compounds are removed in a water bath at 2 mbar / 40 ° C. The crude Boc-protected material is dissolved in 15 ml of 4M HCl in dioxane overnight. The crude product is purified by preparative HPLC.

(I-o): 310 mg (0.47 mmol, 73%) (yield calculated for the four stages)

(I-p): 258 mg (0.38 mmol, 59%) (calculated yield for the four steps)

Procedure 6: Hydroxyacetyl-LO-Methyl-Tyr-D-Pro-NH-2-Ad

0.75 mmol (1.0 equiv.) Of HO-methyl-Tyr-D-Pro-NH-2-Ad from procedure 2c is dissolved in DMF. 0.788 mmol (1.1 equiv.) Of tBuO-Ac-OH is preactivated in DMF by adding 1.1 equiv. of TBTU and 1.9 equiv. by DIPEA. After 4 minutes, the solutions are combined and allowed to react for one hour at room temperature. The reaction mixture is transferred to a separatory funnel with ethyl acetate and water. The aqueous phase is re-extracted with ethyl acetate. The combined organic phases are washed with 5% NaHCO3, ^{1M KHSO 4,} and brine. All volatile compounds are removed in a water bath at 2 mbar / 40 ° C. The crude Boc-protected material is dissolved in 10 ml / 4 M HCl in dioxane for 45 minutes and deprotected by adding 2 x 10 ml of TFA and stirring overnight. The crude product is purified by preparative HPLc.

(I-r): 157 mg (0.32 mmol, 42%)

3. Activity tests

3.1. Inhibition of 11-beta-hydroxysteroid dehydrogenase type 1

Preparation of cell lysates

Stably transfected human embryonic kidney (HEK-293) cells expressing 11 p-HSD1 and hexose-6-phosphate dehydrogenase (the so-called HHH7 clone) were cultured for 48 h in Dulbecco's Modified Eagle's Medium (DMEM) containing 4.5 g / l glucose, 10% fetal calf serum, 100 U / ml penicillin, 0.1 mg / ml streptomycin, 1 x MEM non-essential amino acids, and 10 mM HEPES buffer, pH 7.4. The cells were then washed with phosphate buffered saline and centrifuged for 4 min at 150 x g. After removing the supernatants, the cell pellets were flash frozen on dry ice and stored at -80 ° C until further use.

Assay for activity in cell lysates

Cell lysates were incubated for 10 min at 37 ° C in TS2 buffer (100 mM NaCl, 1 mM EGTA, 1 mM EDTA, 1 mM MgCl ² , 250 mM sucrose, 20 mM Tris-HCl, pH 7.4) in a 22.2 ^ L volume containing the solvent (0.1% DMSO) or the inhibitor at the respective concentration indicated in Table 3-1. Enzyme activities were measured using the following conditions: 192 nM unlabeled cortisone, 8 nM radiolabeled cortisone, 450 µM NADPH.

Reactions were stopped after 10 min by adding excess unlabeled cortisone and cortisol (1: 1.2 mM, in methanol). Steroids were separated by TLC, using methanol-chloroform (1: 9) as solvent, followed by scintillation counting and calculation of substrate concentration. Data were collected from four independent measurements (standard deviation <10%).

Table 3-1: Enzyme Assay Results

3.2. Human Keratinocyte Assay

Cell culture: Primary human skin keratinocytes obtained from CelINTec advanced Cell Systems were maintained in CnT-PR medium at 37 ° C in a humidified atmosphere of 5% CO ² -air. Cells were subcultured before reaching confluence.

Evaluation of 11B-HSD1 activity: Human primary keratinocytes were precultured in complete culture medium (CnT-PR, CellNTec) to 90% confluence. Subsequently, the cells were washed twice with PBS buffer to remove the remaining corticosteroids and the medium was exchanged to medium without custom hydrocortisone. The cells were then treated with 1000 nM cortisone in combination with different concentrations of inhibitors as indicated in Table 3-2. About 48 h later, the cell culture supernatant was harvested and cortisol levels were assessed with the cortisol parameter assay kit (R&D Systems) following the protocol instructions and using a Multiskan Ascent plate reader (Labsystems).

Calculation:% 11 p-HSD1 activity remaining = cortisol level with inhibitor / cortisol level without inhibitor) * 100% Table 3-2: Results

3.3. Total dermal collagen after cortisone and cortisone inhibitor treatment

Human skin from abdominal plastic surgery was used. The skin samples were cut into ~ 8 x 3 mm pieces ⁽⁰ x thickness) and cultured until day 6 at an air-liquid interface in a perforated stainless steel washer in contact with a culture medium (medium E of modified Williams), while the culture medium was renewed on day 3. Six skin samples were used for each test sample. Each test sample (4 gl) was applied topically on top of each piece after cleaning the surface with a cotton pad, which was subsequently covered with a 6 ⁰ mm delivery membrane, this procedure was repeated daily. . After 6 days, the skin sections were stained with Picrosirius Red histochemical stain, which stains the collagen fibers purple-red. The papillary dermis was selected for analysis. The different colors of the images were separated using a deconvolution matrix. After deconvolution, only reddish-pink images are used. Within these images, dermal collagen evaluation was performed by estimating both color intensity and distribution with IMAGE J (NIH) analysis software. Two slides from each skin sample were processed by image acquisition and related analysis (ie, 12 images for each treatment).

Table 3-3: Results of Comparison Treatments Against 0.1 Pl Cortisone on Day 6

As can be recovered from the results summarized in Table 3-3, the 11 p-HSD1 inhibitors according to the present invention counteracted cortisone activity by restoring total collagen in the papillary dermis.

4. References

As references, 1-Adamantyl substituted compounds of formula 1 have been prepared as summarized in Table 4-1 in analogy to the procedures outlined above and tested in the enzymatic assay. As can be recovered from Table 4-1, these compounds showed little or no activity at all (at 1 gM concentration).

Table 4-1: Comparative data

5. Cosmetic composition

Table 5-1 summarizes exemplary O / W emulsions, in which a compound selected from the group of (Ia) to (Is) as summarized in Table 1 (respectively Table 3-1), is incorporated in the indicated amount .

Table 5-1: Exemplary O / W Emulsion

Claims (15)

1. A compound of formula (I)

where n, m, and p are independently 0 or 1, if n is 1, then q is 1 or 2, R1 is selected from the group consisting of H, C ¹ -C ⁶ acyl, or hydroxyacetyl, R2 is H or C ¹ -C ⁶ alkyl, and R3 is selected from the group consisting of H, C ¹ -C ^6, aralkyl C ¹ -C ⁶ heteroarylalkyl ^C1 - ^C6 and biphenylalkyl C ¹ -C 6, in which the aromatic residue aryl, heteroaryl or biphenyl may be optionally substituted, or a cosmetically acceptable salt thereof. The compound according to claim 1, wherein the optionally substituted aryl, heteroaryl or biphenyl aromatic residue is substituted with a substituent selected from the group consisting of halogen, hydroxy, nitro, cyano, C ¹ -C ⁶ alkyl, alkoxy ^C1 - ^C6 alkanoyloxy and ^C1 - ^C6. The compound according to claim 1, wherein the heteroaryl and biphenyl aromatic residues are unsubstituted and the aryl aromatic residue is substituted with a substituent selected from the group consisting of F, Cl, hydroxy, cyano, C ^{1 alkyl} -C ³ alkoxy C ¹ -C ³ alkanoyloxy and C ¹ -C ^3, preferably of the group consisting of F, hydroxy, cyano, (m) ethoxy and acetoxy. 4. The compound according to any one of claims 1 to 3, wherein R1 is selected from the group consisting of H and a C ¹ -C ² acyl, preferably H and acetyl. 5. The compound according to any one of claims 1 to 4, wherein R2 is selected from the group consisting of H and a C ¹ -C ² alkyl, preferably H and methyl. 6. The compound according to any one of claims 1 to 5, wherein R3 is selected from the group consisting of H, C ¹ -C ² alkyl, C ¹ -C ² aralkyl, heteroaryl C ¹ -C ² and C biphenylalkyl ¹ -C ² . 7. The compound according to any one of claims 1 to 6, wherein R3 is selected from the group consisting of H, methyl, 3-hydroxybenzyl, 4-hydroxybenzyl, 4-methoxybenzyl, 4-ethoxybenzyl, 4-acetoxybenzyl , 4-fluorobenzyl, 2-cyanobenzyl, 4-cyanobenzyl, 1,1'-biphenyl-3-ylmethyl and 1 H-indol-3-ylmethyl. The compound according to any one of claims 1 to 7, wherein the cosmetically acceptable salt is an acetate or a trifluoroacetate. 9. The compound of formula (I) according to any one of claims 1 to 8, which is a compound of formula (II), (III) or (IV)

10. The compound of formula (I) according to claim 1, which is (R) -1- (3-acetamidopropanoyl) -N- (adamantan-2-yl) pyrrolidine-2-carboxamide (I-a), (R) -1- (acetylglycyl) -N- (adamantan-2-yl) pyrrolidine-2-carboxamide (I-b), (R) -1- (L-tyrosyl) -N- (adamantan-2-yl) pyrrolidine-2-carboxamide (I-c) trifluoroacetate, (R) -1- (L-tryptophyl) -N- (adamantan-2-yl) pyrrolidine-2-carboxamide (I-d) trifluoroacetate (R) -1- (acetyl-L-tyrosyl) -N- (adamantan-2-yl) pyrrolidine-2-carboxamide (I-e), 4 - ((S) -2-acetamido-3 - ((R) -2- (adamantan-2-ylcarbamoyl) pyrrolidin-1-yl) -3-oxopropyl) phenyl acetate (If), (R) trifluoroacetate -1 - ((S) -3 - ([1,1'-biphenyl] -3-yl) -2-aminopropanoyl) -N- (adamantan-2-yl) pyrrolidine-2-carboxamide (Ig), (R ) -1 - ((S) -2-acetamido-3- (4-fluorophenyl) propanoyl) -N- (adamantan-2-yl) -pyrrolidine-2-carboxamide (Ih), (R) -N- trifluoroacetate (adamantan-2-yl) -1 - ((S) -2-amino-3- (3-hydroxyphenyl) propanoyl) pyrrolidine-2-carboxamide (Ii), (R) -N- (adamantan-2- trifluoroacetate yl) -1 - ((S) -2- (2-aminoacetamido) -3- (4-methoxyphenyl) -propanoyl) pyrrolidine-2-carboxamide (Ij), (R) -N- (adamantan-2-yl) -1 - ((S) -2-amino-3- (4-ethoxyphenyl) propanoyl) pyrrolidine-2-carboxamide trifluoroacetate (Ik), (R) -1 - ((S) -2-acetamido-3- (4-cyanophenyl) -propanoyl) -N- (adamantan-2-yl) pyrrolidine-2-carboxamide (Il), (R) -1 - ((S) -2-acetamido-3- (4-methoxyphenyl) -propanoyl) -N- (adamantan-2-yl) pyrrolidine-2-carboxamide (In), (R) - bistrifluoroacetate N- (adamantan-2-yl) -1- (2- (2 - ((S) -2-aminopropanamido) acetamido) ethyl) pyrrolidine-2-carboxamide (Io), (R) -N- (adamantan-2-yl) -1- (2 - ((S) -2- (2-aminoacetamido) propanamido) ethyl) pyrrolidine-2-carboxamide (I-p) bistrifluoroacetate, (R) -N- (adamantan-2-yl) -1 - (glycyl-L-tryptopyl) pyrrolidine-2-carboxamide (I-q) trifluoroacetate, (R) -N- (adamantan-2-yl) -1 - ((S) -2- (2-hydroxyacetamido) -3- (4-methoxyphenyl) propanoyl) -pyrrolidine-2-carboxamide (I-r) trifluoroacetate, (R) -1 - ((S) -2-acetamido-3- (2-cyanophenyl) -propanoyl) -N- (adamantan-2-yl) pyrrolidine-2-carboxamide (I-s). 11. A cosmetic composition comprising at least one compound according to any one of claims 1 to 10 and a cosmetically acceptable carrier. 12. The cosmetic composition according to claim 11, characterized in that the total amount of the at least one compound of formula (I) is selected in the range of approximately 0.00001 to 0.5% by weight, more preferably in the range of 0.0001 to 0.25% by weight, much more preferably in the range of 0.0001 to 0.1% by weight, based on the total weight of the cosmetic composition. 13. Cosmetic use of compound of formula (I)

where n, m, and p are independently 0 or 1, if n is 1, then q is 1 or 2, R1 is selected from the group consisting of H, C ¹ -C ⁶ acyl, or hydroxyacetyl, R2 is H or C ¹ -C ⁶ alkyl, and R3 is selected from the group consisting of H, C ¹ -C ^6, aralkyl C ¹ -C ⁶ heteroarylalkyl ^C1 - ^C6 and biphenylalkyl C ¹ -C 6, in which the aromatic residue aryl, heteroaryl or biphenyl may be optionally substituted, or a cosmetically acceptable salt thereof as an 11 p-HSDI inhibitor. 14. Cosmetic use of a compound of formula (I)

where n, m, and p are independently 0 or 1, if n is 1, then q is 1 or 2, R1 is selected from the group consisting of H, C ¹ -C ⁶ acyl, or hydroxyacetyl, R2 is H or C ¹ -C ⁶ alkyl, and R3 is selected from the group consisting of H, C ¹ -C ^6, aralkyl C ¹ -C ⁶ heteroarylalkyl ^C1 - ^C6 and biphenylalkyl C ¹ -C 6, in which the aromatic residue aryl, heteroaryl or biphenyl may be optionally substituted, or a cosmetically acceptable salt thereof for the treatment and prevention of defects in the structure and function of the skin induced by (photo) aging. 15. Method for smoothing wrinkles and fine lines and / or reducing their volume and depth, said method comprising the step of applying a cosmetic composition according to claims 11 or 12 to the affected area.